Abstract The burden of falciparum malaria in sub-Saharan Africa remains unacceptably high despite significant gains in malaria control over the last 15 years. An improved ability to both predict which combinations of interventions are most likely to have the greatest benefit and to accurately evaluate their effects would be of enormous benefit. However, predictions are currently limited by gaps such as poor characterization of relationships between exposure to sporozoite-infected mosquitoes, rates of establishment of blood stage infection, and the clinical consequences of infection, including the crucial impact of antimalarial immunity. In this project, we will take advantage of unique access to linked entomologic, parasitologic, human genomic, and clinical data from intensive cohorts in different regions of Uganda. Importantly, cohorts will be established in sites where changes in community interventions are planned. Using cohort data, we will quantify the impact of environmental and host factors on the establishment and maintenance of infection, and define a serologic profile by which host immunity, a key host factor, can be measured. Central to these efforts will be our ability to detect, distinguish, and follow genetically distinct parasites in the blood of individuals over time, allowing us to accurately measure the force of infection (rate of acquisition of blood stage infections), to follow the trajectory of these infections within a host, and to relate these metrics to entomologic, epidemiologic, and clinical outcome data. We will then integrate these individual-level relationships to characterize their epidemiologic consequences and model the impact of interventions at the population level. This study has 2 aims: 1) To characterize factors determining the malarial force of infection in intensively studied cohorts at different sites in Uganda. We will derive estimates of sporozoite exposure in individuals living in malaria endemic areas, genotype parasites infecting them to derive measures of the force of infection, and evaluate human genetic polymorphisms in all cohort members using a genome-wide approach. With these data, we will determine the relationship between sporozoite exposure and the force of infection, a key relationship in predicting the effect of vector control interventions, and assess the impact of host factors including genetics, age, and recent changes in exposure on this relationship. 2) To determine factors affecting the duration, density, and clinical consequences of blood stage malaria infection in Uganda. Using quantitative PCR and parasite genotyping data, we will determine the impact of host factors such as genetics, age, and prior exposure on blood stage immunity as well as anemia. We will determine how these relationships vary in different epidemiologic settings, including before and after changes in communitywide interventions. In addition, we will define a serologic profile associated with blood stage immunity by measuring responses to P. falciparum proteins by microarray.